Assuntos
Congêneres do Estradiol/síntese química , Indóis/síntese química , Animais , Densidade Óssea/efeitos dos fármacos , Linhagem Celular , Congêneres do Estradiol/química , Congêneres do Estradiol/metabolismo , Congêneres do Estradiol/farmacologia , Feminino , Indóis/química , Indóis/metabolismo , Indóis/farmacologia , Modelos Moleculares , Tamanho do Órgão , Ovariectomia , Ensaio Radioligante , Ratos , Relação Estrutura-Atividade , Transfecção , Útero/efeitos dos fármacosRESUMO
Several novel functionalized adamantyl aryl- and heteroarylpiperazine derivatives were prepared and examined in various receptor binding and behavioral tests to determine their serotonin receptor activities. Many compounds demonstrated modest to high affinity for 5-HT(1A) receptors, with compounds 9, 13, 23, 33, 34, and 43 being the most potent at this site. Compound 1, 2-[4-(2-pyrimidinyl)-1-piperazinyl]ethyl adamantyl-1-carboxylate, demonstrated relatively high affinity for 5-HT(1A) receptors (K(i) = 8 nM) and acceptable selectivity versus D(2) receptors (K(i) = 708 mM); however, it lacked in vivo activity in serotonergic behavioral models. In contrast, compounds 9 (WY-50,324, SEB-324, adatanserin), adamantyl-1-carboxylic acid 2-[4-(2-pyrimidinyl)-1-piperazinyl]ethylamide, and 13, adamantyl-1-carboxylic acid 2-[4-(2-methoxyphenyl)-1-piperazinyl]ethylamide, demonstrated high affinity for 5-HT(1A) binding sites (K(i) = 1 nM for both) and moderate affinity for 5-HT(2) receptors (K(i) = 73 and 75 nM, respectively). Both compounds also demonstrated partial 5-HT(1A) agonist activity in vivo in rat serotonin syndrome and 5-HT(2) antagonist activity in quipazine- and DOI-induced head shake paradigms. The selective 5-HT(1A) partial agonist and 5-HT(2) antagonist activity of 9 was accompanied by significant anxiolytic activity in an animal conflict model. On the basis of this profile, compound 9 entered development as a combined anxiolytic and antidepressant agent.
Assuntos
Ansiolíticos/síntese química , Antidepressivos/síntese química , Piperazinas/síntese química , Receptores de Serotonina/efeitos dos fármacos , Animais , Ansiolíticos/química , Ansiolíticos/farmacologia , Antidepressivos/química , Antidepressivos/farmacologia , Masculino , Modelos Moleculares , Piperazinas/química , Piperazinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/classificação , Análise Espectral , Relação Estrutura-AtividadeRESUMO
1'-Substituted spiro[fluorene-9,3'-pyrrolidine-2',5'-diones], 1',1''' - (1,4-piperazinediyldimethylene) bis[spiro[fluorene-9,3'-pyrrolidine-2',5'-dione]], and 1'-arylspiro[fluorene-9,3'-pyrrolidines] were synthesized from spiro[fluorene-9,3'-tetrahydrofuran-2',5'-dione]. The rat passive cutaneous anaphylaxis assay showed that one compound possessed slight antiallergic activity. Synthesis of 3-substituted 1-aryl-4-oxospiro[azetidine-2,9'-fluorenes] and 1,1''-p-phenylenebis[4-oxospiro[azetidine-2,9'-fluorenes]] was achieved via the reaction of appropriate N-fluorenylideneanilines with tert-butylcyanoketene and cyclopentamethyleneketene, respectively.
